tbuckley/cabot-search huggingface dataset:
Siglec-9<sup>+</sup>tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer
Authors: Yiying Wang, Mengdi He, Chen Zhang, Kankan Cao, Guodong Zhang, Moran Yang, Yan Huang, Wei Jiang, Haiou Liu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC. Methods Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9 + TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays. Results Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9 + TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9 + TAMs with protumorigenic phenotypes. Siglec-9 + TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8 + T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8 + T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9 + TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8 + T cells in tissues with higher Siglec-9 + TAMs. Conclusions Siglec-9 + TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9 + TAMs as a therapeutic target is worth further exploration.
Two cases of extensively drug-resistant (XDR) Neisseria gonorrhoeae infection combining ceftriaxone-resistance and high-level azithromycin resistance, France, November 2022 and May 2023
Authors: Clara Maubaret, François Caméléna, Manel Mrimèche, Aymeric Braille, Mathilde Liberge, Mary Mainardis, Clémence Guillaume, Franck Noel, Cécile Bébéar, Jean-Michel Molina, Florence Lot, Emilie Chazelle, Béatrice Berçot
Journal: Eurosurveillance (2023)

We report two extensively drug-resistant (XDR) Neisseria gonorrhoeae (NG) isolates combining high-level resistance to azithromycin and resistance to ceftriaxone, obtained in France from two heterosexual patients, one of whom returned from Cambodia. Whole genome sequencing identified MLST ST16406, the mosaic penA-60.001 which caused ceftriaxone resistance in the internationally spreading FC428 clone, and the A2059G mutation in the 23S rRNA gene. The NG isolates F93 and F94 were related to XDR isolates detected in Austria and the United Kingdom in 2022.
Bipolar At-Risk Criteria and Risk of Bipolar Disorder Over 10 or More Years
Authors: Aswin Ratheesh, Dylan Hammond, Michael Watson, Jennifer Betts, Emma Siegel, Patrick McGorry, Michael Berk, Susan Cotton, Andrew Chanen, Barnaby Nelson, Andreas Bechdolf
Journal: JAMA Network Open (2023)

Predicting the onset of bipolar disorder (BD) could facilitate preventive treatments. Among risk measures, bipolar at-risk (BAR) criteria have shown promise in predicting onset of bipolar disorder in the first year in clinical cohorts; however, it is not known whether BAR criteria are associated with the onset of BD in the longer term.To assess the association of BAR criteria with onset of BD over 10 to 13 years follow-up.This prospective cohort study, completed between May 1, 2020, and November 7, 2022, included consenting people seeking help for nonpsychotic major mental health difficulties, including mood, personality, and substance use disorders, who were originally recruited at ages 15 to 25 years from a tertiary youth mental health setting in metropolitan Melbourne, Victoria, Australia, from May 1, 2008, to September 30, 2010.Meeting BAR criteria at baseline. Criteria included subthreshold mania, cyclothymic features, subthreshold depression, and family history of BD. A matched clinical comparison group was recruited from the same help-seeking population.The primary outcome was expert consensus diagnosis of BD I or II based on the Mini International Neuropsychiatric Interview, self-reported information collected through online assessments, and linked data on mental health service utilization in Victoria over 10 to 13 years of follow-up.Among 69 eligible participants, follow-up data were available for 60 (88.2%). The mean (SD) age at the end of follow-up was 32.9 (2.8) years, and 49 (81.7%) were women. A total of 28 participants met BAR criteria, and 32 were in the comparison group. In the BAR group, 8 patients (28.6%) developed BD over a mean (SD) of 11.1 (0.7) years of follow-up, and no patients in the comparison group developed BD. The risk of developing BD was higher in the BAR group than in the non-BAR group (χ21 = 70.0; P < .001). The proportions of transitions to BD were equal in the first and second halves of the follow-up period.In this cohort study of participants seeking care for mental health difficulties, patients meeting the BAR criteria were significantly more likely to transition to BD over a decade after ascertainment compared with patients not meeting the BAR criteria. The findings suggest that those meeting BAR criteria may benefit from longer-term monitoring and support. Evaluation of predictive properties in longer-term studies using a risk measure will help with implementation of BAR criteria in clinical settings.
The re-emergence of influenza following the COVID-19 pandemic in Victoria, Australia, 2021 to 2022
Authors: Catherine GA Pendrey, Janet Strachan, Heidi Peck, Ammar Aziz, Jean Moselen, Rob Moss, Md Rezanur Rahaman, Ian G Barr, Kanta Subbarao, Sheena G Sullivan
Journal: Eurosurveillance (2023)

BackgroundCOVID-19 pandemic mitigation measures, including travel restrictions, limited global circulation of influenza viruses. In Australia, travel bans for non-residents and quarantine requirements for returned travellers were eased in November 2021, providing pathways for influenza viruses to be re-introduced.AimWe aimed to describe the epidemiological and virological characteristics of the re-emergence of influenza in Victoria, Australia to inform public health interventions.MethodsFrom 1 November 2021 to 30 April 2022, we conducted an epidemiological study analysing case notification data from the Victorian Department of Health to describe case demographics, interviewed the first 200 cases to establish probable routes of virus reintroduction and examined phylogenetic and antigenic data to understand virus diversity and susceptibility to current vaccines.ResultsOverall, 1,598 notifications and 1,064 positive specimens were analysed. The majority of cases (61.4%) occurred in the 15-34 years age group. Interviews revealed a higher incidence of international travel exposure during the first month of case detections, and high levels of transmission in university residential colleges were associated with return to campus. Influenza A(H3N2) was the predominant subtype, with a single lineage predominating despite multiple importations.ConclusionEnhanced testing for respiratory viruses during the COVID-19 pandemic provided a more complete picture of influenza virus transmission compared with previous seasons. Returned international travellers were important drivers of influenza reemergence, as were young adults, a group whose role has previously been under-recognised in the establishment of seasonal influenza epidemics. Targeting interventions, including vaccination, to these groups could reduce future influenza transmission.
Physical Activity Intervention for Leisure-Time Activity Levels Among Older Adults
Authors: Nanyan Li, Qin Ye, Qian Deng, Yufei Wang, Julinling Hu, Xianlan Li, Qianqian Liu, Meili Jiang, Xing Zhao, Junmin Zhou
Journal: JAMA Network Open (2023)

Current randomized trial evidence of the effects of physical activity interventions in older adults is mainly from developed countries, with little reliable evidence from low- and middle-income countries, such as China, where race, culture, and lifestyles differ substantially from those in Western populations.To evaluate the effects of a multilevel intervention for increasing leisure-time activity levels in Chinese older adults.This cluster randomized trial was conducted from May 2021 to May 2023, including an 8-week intervention period and a follow-up period of 24 months. Eight villages in China were randomly assigned to the intervention (4 villages) or the control (4 villages) group. Potentially eligible participants were 60 years or older. A total of 511 older adults from the selected 8 villages were enrolled.The intervention group received an 8-week socioecological model-based intervention, comprising individual, interpersonal, and community-level components, whereas the control group did not.The primary outcome was the change in leisure-time activity at 8 weeks, measured by the Physical Activity Scale for the Elderly (PASE). Possible PASE scores for leisure-time activity range from 0 to 502, with higher scores indicating higher activity levels.A total of 511 older adults from 8 villages were recruited and randomly allocated to the intervention (240 participants, 4 villages) or control (271 participants, 4 villages) groups. The mean (SD) age was 70.95 (5.72) years, and 284 (55.6%) were female participants. Seven serious adverse events (unrelated deaths) were reported. Participants in the intervention group increased leisure-time activity more than those in the control group, with a mean difference in PASE scores of 13.74 points (95% CI, 8.58-18.91 points) between the groups at 8 weeks (P < .001). Significant differences in leisure-time activity were also found over 24 months (mean difference in scores at 4 weeks, 11.66 points; 95% CI, 6.41-16.90 points; P < .001; at 6 months, 12.35 points; 95% CI, 7.19-17.50 points; P < .001; at 12 months, 11.55 points; 95% CI, 6.32-16.78 points; P < .001; and at 24 months, 14.51 points; 95% CI, 9.28-19.75 points; P < .001).In this cluster randomized trial, the multilevel intervention was effective in promoting leisure-time activity over 24 months of follow-up in older adults from China. This finding suggests that implementation of such interventions could be an important step in addressing physical inactivity in older adults in low- and middle-income countries.Chinese Clinical Trial Registry Identifier: ChiCTR2100045653.
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition
Authors: Charles Bayard, Eleonora Segna, Maxime Taverne, Antoine Fraissenon, Quentin Hennocq, Baptiste Periou, Lola Zerbib, Sophia Ladraa, Célia Chapelle, Clément Hoguin, Sophie Kaltenbach, Patrick Villarese, Vahid Asnafi, Christine Broissand, Ivan Nemazanyy, Gwennhael Autret, Nicolas Goudin, Christophe Legendre, François-Jérôme Authier, Thomas Viel, Bertrand Tavitian, Cyril Gitiaux, Sylvie Fraitag, Jean-Paul Duong, Clarisse Delcros, Bernard Sergent, Arnaud Picard, Michael Dussiot, Laurent Guibaud, Roman Khonsari, Guillaume Canaud
Journal: The Journal of Experimental Medicine (2023)

Hemifacial myohyperplasia (HFMH) is a rare cause of facial asymmetry exclusively involving facial muscles. The underlying cause and the mechanism of disease progression are unknown. Here, we identified a somatic gain-of-function mutation of PIK3CA in five pediatric patients with HFMH. To understand the physiopathology of muscle hypertrophy in this context, we created a mouse model carrying specifically a PIK3CA mutation in skeletal muscles. PIK3CA gain-of-function mutation led to striated muscle cell hypertrophy, mitochondria dysfunction, and hypoglycemia with low circulating insulin levels. Alpelisib treatment, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of endocrine anomalies. Based on these findings, we treated the five HFMH patients. All patients demonstrated clinical, esthetical, and radiological improvement with proof of target engagement. In conclusion, we show that HFMH is due to somatic alteration of PIK3CA and is accessible to pharmacological intervention.
Improved early outcome prediction by MRI-based 3D tumor volume assessment in patients with CNS lymphomas
Authors: Eliza M Lauer, Ella Riegler, Jurik A Mutter, Stefan K Alig, Sabine Bleul, Julia Kuehn, Lavanya Ranganathan, Christian Klingler, Theo Demerath, Urs Würtemberger, Alexander Rau, Jakob Weiß, Michel Eisenblaetter, Fabian Bamberg, Marco Prinz, Jürgen Finke, Justus Duyster, Gerald Illerhaus, Maximilian Diehn, Ash A Alizadeh, Elisabeth Schorb, Peter C Reinacher, Florian Scherer
Journal: Neuro-Oncology (2023)

Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment.
Which Small Molecule? Selecting Chemical Probes for Use in Cancer Research and Target Validation
Authors: Mary M. Mader, Joachim Rudolph, Ingo V. Hartung, David Uehling, Paul Workman, William Zuercher
Journal: Cancer Discovery (2023)

Abstract Small-molecule chemical “probes” complement the use of molecular biology techniques to explore, validate, and generate hypotheses on the function of proteins in diseases such as cancer. Unfortunately, the poor selection and use of small-molecule reagents can lead to incorrect conclusions. Here, we illustrate examples of poor chemical tools and suggest best practices for the selection, validation, and use of high-quality chemical probes in cancer research. We also note the complexity associated with tools for novel drug modalities, exemplified by protein degraders, and provide advice and resources to facilitate the independent identification of appropriate small-molecule probes by researchers. Significance: Validation of biological targets and pathways will be aided by a shared understanding of the criteria of potency, selectivity, and target engagement associated with small-molecule reagents (“chemical probes”) that enable that work. Interdisciplinary collaboration between cancer biologists, medicinal chemists, and chemical biologists and the awareness of available resources will reduce misleading data generation and interpretation, strengthen data robustness, and improve productivity in academic and industrial research.
Preliminary results on an autochthonous dengue outbreak in Lombardy Region, Italy, August 2023
Authors: Irene Cassaniti, Guglielmo Ferrari, Sabrina Senatore, Eva Rossetti, Francesco Defilippo, Manuel Maffeo, Luigi Vezzosi, Giulia Campanini, Antonella Sarasini, Stefania Paolucci, Antonio Piralla, Davide Lelli, Ana Moreno, Maira Bonini, Marcello Tirani, Lorenzo Cerutti, Stefano Paglia, Angelo Regazzetti, Marco Farioli, Antonio Lavazza, Marino Faccini, Francesca Rovida, Danilo Cereda, Fausto Baldanti
Journal: Eurosurveillance (2023)

In August 2023, six locally acquired dengue virus 1 infections were detected in Lodi province, Lombardy Region, in northern Italy, where the vector Aedes albopictus is present. Four cases were hospitalised, none died. The viruses clustered with Peruvian and Brazilian strains collected between 2021 and 2023. This preliminary report highlights the importance of continued integrated surveillance of imported vector-borne virus infections and the potential for tropical disease outbreaks in highly populated regions of northern Italy where competent vectors are present.
Correction: ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors Across Tumor Types
Authors: Anderly C. Chüeh, Janson W.T. Tse, Michael Dickinson, Paul Ioannidis, Laura Jenkins, Lars Togel, BeeShin Tan, Ian Luk, Mercedes Davalos-Salas, Rebecca Nightingale, Matthew R. Thompson, Bryan R.G. Williams, Guillaume Lessene, Erinna F. Lee, Walter D. Fairlie, Amardeep S. Dhillon, John M. Mariadason
Journal: Clinical Cancer Research (2023)

In the original version of this article (1), Fig. 3A used the same b-tubulin control for FOS and JUN, and the legend for Fig. 4 did not clarify that the same HCT116 b-
Precision Oncology Comes of Age: Designing Best-in-Class Small Molecules by Integrating Two Decades of Advances in Chemistry, Target Biology, and Data Science
Authors: Darrin D. Stuart, Angel Guzman-Perez, Natasja Brooijmans, Erica L. Jackson, Gregory V. Kryukov, Adam A. Friedman, Axel Hoos
Journal: Cancer Discovery (2023)

Small-molecule drugs have enabled the practice of precision oncology for genetically defined patient populations since the first approval of imatinib in 2001. Scientific and technology advances over this 20-year period have driven the evolution of cancer biology, medicinal chemistry, and data science. Collectively, these advances provide tools to more consistently design best-in-class small-molecule drugs against known, previously undruggable, and novel cancer targets. The integration of these tools and their customization in the hands of skilled drug hunters will be necessary to enable the discovery of transformational therapies for patients across a wider spectrum of cancers. Target-centric small-molecule drug discovery necessitates the consideration of multiple approaches to identify chemical matter that can be optimized into drug candidates. To do this successfully and consistently, drug hunters require a comprehensive toolbox to avoid following the "law of instrument" or Maslow's hammer concept where only one tool is applied regardless of the requirements of the task. Combining our ever-increasing understanding of cancer and cancer targets with the technological advances in drug discovery described below will accelerate the next generation of small-molecule drugs in oncology.
Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice
Authors: Simon Lebek, Xurde M. Caravia, Francesco Chemello, Wei Tan, John R. McAnally, Kenian Chen, Lin Xu, Ning Liu, Rhonda Bassel-Duby, Eric N. Olson
Journal: Circulation (2023)

Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca
ANGPTL3 Deficiency and Risk of Hepatic Steatosis
Authors: Laura D’Erasmo, Michele Di Martino, Thomas Neufeld, Tyler J. Fraum, Chul Joo Kang, Kendall H. Burks, Alessia Di Costanzo, Ilenia Minicocci, Simone Bini, Marianna Maranghi, Giovanni Pigna, Giancarlo Labbadia, Jie Zheng, Davide Fierro, Anna Montali, Fabrizio Ceci, Carlo Catalano, Nicholas O. Davidson, Giuseppe Lucisano, Antonio Nicolucci, Marcello Arca, Nathan O. Stitziel
Journal: Circulation (2023)

ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3.
Cobweb‐Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment
Authors: Yongjie Jiao, Xiaojing Li, Xingxing Liu, Chaojing Li, Xiao Yang, Xuwei Sun, Fujun Wang, Lu Wang
Journal: Advanced Healthcare Materials (2023)

Abstract In soft tissue repair, fibrosis can lead to repair failure and long‐term chronic pain in patients. Excessive mechanical stimulation of fibroblasts is one of the causes of fibrosis during abdominal wall regeneration. Inspired by the cobweb, a polycaprolactone beaded fiber is prepared by electrospinning. The cobweb‐inspired structure attenuates the mechanical stimulation of cells under a dynamic environment. Nano‐protrusions are introduced into the scaffold for further inhibition of fibrosis by self‐induced crystallization. A machine is built for in vitro dynamic culture and rat abdominal subcutaneous embedding experiments are performed to verify the inhibiting effect of fibrosis in a dynamic environment in vivo. Results show that the expression of integrin β1 and α‐smooth muscle actin is inhibited by the cobweb‐inspired structure under dynamic culture. The results of hematoxylin and eosin and Masson's trichrome indicate that the cobweb‐inspired structure has a good inhibitory effect on fibrosis in a dynamic environment in vivo. In general, the cobweb‐inspired scaffold with nano‐protrusions has a good ability to inhibit fibrosis under both static and dynamic environments. It is believed that the scaffold has promising applications in the field of inhibiting fibrosis caused by mechanical stimulation.
Intratumoral Bacteria as Mediators of Cancer Immunotherapy Response
Authors: Karen S. Sfanos
Journal: Cancer Research (2023)

Abstract Multiple lines of evidence spanning from animal models to human clinical trials indicate that the microbiome influences cancer immunotherapy response. Whereas initial studies focused exclusively on the gastrointestinal (gut) microbiota–tumor axis, more recent studies have examined the possibility that bacteria located within tumor cells or within the tumor microenvironment mediate cancer treatment response. Strikingly, this phenomenon has been demonstrated in cancers that arise in anatomic locations that are traditionally thought to be devoid of resident microbiota. In this issue of Cancer Research, Wu and colleagues examine the effects of intratumoral bacterial signatures on treatment response in the setting of neoadjuvant chemotherapy combined with immunotherapy (NACI) in the treatment of esophageal squamous cell carcinoma (ESCC). The study reports that intratumoral Streptococcus, presumably due to bacterial translocation from the gut, predicts the treatment efficacy of NACI in murine models as well as individuals with ESCC. These new findings further highlight the possibility that the presence of intratumoral microbes as well as their associated metabolites influence both the tumor immune microenvironment and immunotherapy efficacy. These findings also raise the intriguing possibility of cross-reactivity between tumor and bacterial antigens. Given that the gut microbiome is potentially a modifiable factor via diet, prebiotics/probiotics, and fecal microbiota transplantation, among other strategies, further exploration into the mechanisms by which gut and/or intratumoral bacteria influence antitumor immunity is certainly warranted. See related article by Wu et al., p. 3131